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CRS assay, similar patterns of response were observed across laboratories that replicated the
cytokine release patterns previously published for the respective clinical therapeutic mAbs
(Vessillier et al., 2020). Taken together, it is crucial for patient safety that CRS potential of
agonistic mAbs is evaluated prior to FIH.
TLS resulting from rituximab therapy has been reported in patients with chronic lympho-
cytic leukemia (Yang et al., 2012). TLS is a constellation of metabolic abnormalities: hyperuri-
cemia, azotemia, hyperkalemia, hyperphosphatemia, and hypocalcemia, which can lead to
nephrotoxicity and renal failure (due to crystallization of uric acid and calcium phosphate
in the renal tubules). Accurate prediction of patients who will develop TLS cannot be
made effectively from nonclinical studies due to the absence of tumors (Grimm et al., 2010).
Hypersensitivity reactions
An inherent liability of biotherapeutics resides in their ability to stimulate the immune sys-
tem, which may lead to hypersensitivity reactions (HSR) (Szebeni, 2012). HSR is a major and
potentially lethal hemo-incompatibility, the symptoms of which involve almost all organ sys-
tems. In addition, infusion reactions can either represent hypersensitivity reactions that arise
after prior exposure of the reactogenic drug to blood and involves immune memory in the
form of specific IgE formation, or involve no IgE and may arise, at least in part, as a conse-
quence of activation of the complement system - complement activation-related pseudoal-
lergy (CARPA) (Neumeister et al., 2001). CARPA occurs primarily during first infusion of
the drug, although it can also occur during subsequent administrations. Szebeni (2012) out-
lined available methods for complement activation and CARPA testing in vitro and in vivo,
namely, the ELISA of complement cleavage products (C3a, C5a, C4d, Bb, SC5b-9), the hemo-
lytic (CH50) complement assay, flow cytometry measurement of basophil leukocyte activa-
tion, multiplex bead assay for complement activation by-products, the porcine assay of
nanoparticle-induced cardiopulmonary distress and other CARPA tests in animals. The
proven parallelisms between complement activation and HSR in vivo provide a rationale
for using these tests as predictors of infusion hypersensitivity.
Can we better address potential off-target toxicity?
As previously discussed, toxicities related to biotherapeutics are often caused by exagger-
ated pharmacologic effect, but unexpected toxicity can also be caused either by binding to the
intended target in an unexpected tissue, or by off-target binding. Due to the high target spec-
ificity of biotherapeutics, off-target binding is rare, but it does occur, and a diligent nonclin-
ical safet y program must assess this risk.
One method frequently used for assessing both target distribution and unexpected binding
is the tissue cross-reactivity (TCR) assay. The TCR assay is based on immunohistochemistry
(IHC) binding by the intended drug candidate to a panel of frozen human tissues. ICH S6(R1)
recommends that a TCR assessment or a similar study is included in the nonclinical safety
assessment package for mAbs and similar proteins (ICH S6(R1), 2011). It is recognized that
binding by the intended drug candidate to a tissue or cell type does not necessarily indicate
4. Early de-risking strategy for biotherapeutics116
I. Development of biopharmaceuticals
that there would be biological activity, and the results should be interpreted in the context of
target localization, frequency, affinity, etc.
It is also recognized that not all mAbs or antibo dy-like proteins are suitable IHC reagents,
and for some drug modalities, or for some targets, it is not possible to develop reliable IHC
assays (Leach et al., 2010; ICH S6(R1), 2011). Novel screening technologies may be more use-
ful in these cases. Screening assessment for off-target binding can be performed on flow
cytometer-based platforms or using a cell microarray such as the one developed by Retroge-
nix. The Retrogenix platform utilizes HEK cells transfected to express human cell surface re-
ceptors and secreted proteins, currently 6500 proteins can be individually expressed. Binding
of the intended drug candidate to the majority of extracellular proteins can thus be assessed,
and any interactiondexpected or unexpecteddcan be investigated in detail. Even more
novel, in silico-based methods, are being developed for prediction of off-target binding during
antibody sequence design (Musnier et al., 2022). These methods can predict the specific
epitope that is recognized by a mAb based on the amino acid sequence of its complementarity
determining regions, and thereby predict what potential other antigens may be recognized by
the mAb.
Hematologic toxicity
An unintended toxicity resulting from administration of biotherapeutics is hematologic
toxicity. A meta-analysis of safety reporting databases from 1995 to 2008 estimated that
biotherapeutic-associated adverse events of the “blood and lymphatic system” was 1.4-fold
higher than that of small molecule pharmaceuticals (Everds and Tarrant, 2013). However,
a comprehensive overview of the hematologic toxicities associated with immune checkpoint
inhibitors (ICIs) (Kroll et al., 2022) shows that such toxicities are rare. ICIs are a class of anti-
neoplastic therapies that have emerged in the last decade that enhance the immune response
against malignant cells. This could be related due to overactive T lymphocytes, autoantibody
production, and cytokine dysregulation, but the exact mechanisms underlying these toxicities
remain uncertain, which poses chal lenges in their management. To address this, Kroll et al.
(2022) suggests that experiences with similar immune-related conditions, such as autoim-
mune hemolytic anemia, immune thrombocytopenia, and idiopathic aplastic anemia, can
be used as a basis for managing these hematologic complications. Managing hematologic tox-
icities associated with ICIs can be particularly challenging as it requires balancing the need to
address the toxicities while ensuring effect ive cancer therapy is maintained or minimally
interrupted. In a survey of oncologic biotherapeutics, hematologic toxicity is second only
to infusion reactions in terms of the most frequent side effects (Klastersky, 2006). Hematotox-
icity can be directly related to the activity of the biotherapeutic, or can be indirect due to auto-
immunity, influence on signaling pathways, ADAs, or other immune system responses
(Table 4.4). In addition, patient factors (including preexisting disease, concu rrent medica-
tions, and genetics) can influence the occurrence of hematotoxicity (Everds and Tarrant,
2013). Pathogenesis of hematologic effects of biotherapeutics are usually unexpected, whether
on-target or off-target (Table 4.4). Biotherapeutics cause hematotoxicity as a result of cellular
activation, cytotoxicity, drug-dependent and independent immune responses, and sequelae
from initiating cytokine and complement cascades (Everds and Tarrant, 2013). Many
Can we better address potential off-target toxicity? 117
I. Development of biopharmaceuticals
TABLE 4.4 Mechanisms of biotherapeutic-induced hematotoxicity.
Biotherapeutic Mechanism Brand name Modality Target RBC NEUT PLT Pan
Abciximab Immune-
mediated
ReoPro Chimeric Fab GP IIb/IIIa X
Adalimumab Humira Human mAb TNFa XXX
Alemtuzumab Campath Humanized mAb CD52 X X X X
AMG X N/A Human mAb Soluble
target
X
anti-CD40L Various Various CD40L X
Anti- EGFL7 N/A Humanized mAb EGFL7 X
CNTO-607 N/A Human mAb IL-13 X
Bevacizumab Avastin Humanized mAb VEGF X X
CAT3888/BL22 N/A PE38 and anti-CD22 immunotoxin CD22 X X
Certolizumab
pegol
Cimzia Humanized mAb TNFa X
Combotox N/A RFB4-dgA and HD37-dgA
immunotoxins
CD19 and CD22 X X
DAB486IL-2 N/A Fusion protein IL-2 and diphtheria
toxin
IL-2R X X
Eculizumab Soliris Humanized mAb C5 X
Efalizumab Raptiva Humanized mAb CD11a X
Etanercept Enbrel TNF Receptor-Fc fusion protein TNFa XXX
Golimumab Simponi Human mAb TNFa X
Heparin Various Extracted glycoprotein Coagulation
factors
X
IFNa2a Various Recombinant protein IFNa2a X X X
IFNa2b Various Recombinant protein IFNa2b X X X
IFNg N/A Recombinant protein IFNg X
IL-10 N/A Recombinant protein IL-10 X
4. Early de-risking strategy for biotherapeutics118
I. Development of biopharmaceuticals
Infliximab Remicade Chimeric mAb TNFa XXX
IVIG Various Polyclonal Ab N/A X X
LY2469298/AME-
133
N/A Humanized mAb, Fc modified CD20 X
LY2541546 N/A Humanized mAb Sclerostin X
mAbY.1 N/A Human mAb Cell based
target
XX
Moxetumomab
pasudotox
Pseudomonas toxin and anti-CD22
immunotoxin
CD22 X X
Muromonab Orthoclone
OKT3
Murine mAb CD3 X X
Ofatumumab Arzerra Human mAb CD20 X X
Omalizumab Xolair Humanized mAb IgE X
Pegylated-IFN Various Pegylated recombinant protein IFN X X X
PEG-rHuMGDF N/A Pegylated recombinant protein Thrombopoiesis X
rhEPO Various Recombinant protein Erythropoiesis X
rhIL-10 N/A Recombinant protein IL-10 X
rHu-TPO N/A Recombinant protein Thrombopoiesis X
RhuMAbv114/
PRO131921
N/A Humanized mAb, Fc modified CD20 X
Rituximab Rituxan,
Mabthera
Chimeric mAb CD20 X X
Streptokinase Streptase Bacterial protein Plasminogen X
Tocilizumab Actemra,
RoActemra
Humanized mAb IL-6R X
Trastuzumab Herceptin Humanized mAb HER2/neu,
ErbB2
XX
Can we better address potential off-target toxicity? 119
I. Development of biopharmaceuticals
biotherapeutics have a complex interactive relationship with their targets (both soluble and
cell-based) and nontargeted blood components. Effects can be immediate, as observed during
intravenous administration, and prolonged due to lengthy systemic exposures, which leads
to increased potential for effects on blood cells. Some of the blood components that are at
the front line for this type of activity are cells and soluble factors that are primed for activity
such as neutrophils, monocytes, platelets, and the complement system by interaction of bio-
therapeutics with cell surface receptors.
Thrombocytopenia is the most commonly observed unexpected hematologic effect among
biotherapeutics. The localization of multimeric complexes of antibodies (mAb or endogenous
antibodies) with multivalent endogenous antigens on the surface of platelets predisposes sub-
jects to the development of thrombocytopenia, sometimes with thrombosis. Multimeric com-
plexes of antibodies have the ability to bind to platelet surfaces through their FcgRIIa
receptors leading to platelet activation and aggregation. The intense platelet activation
induced by these antibody complexes increases thrombin generat ion, thus determining a hy-
percoagulability st ate. This mechanism is responsible for thrombocytopenia and thrombosis
due to heparin and streptokinase and postulated for anti-CD40L molecules and bevacizumab
(Meyer et al., 2009). Since the scope of this review does not allow an exhaustive narrative of
thrombocytopenia following biologic administration, a few case studies are presented below
to highlight utility of animal models to understand antibody-mediated thrombocytopenia in
animals.
Bevacizumab case study
Nonclinical testing in mice did not predict arterial thrombo-embolism in colorectal cancer
patients associated with the antiangiogenic drug bevacizumab). The initial hypothesis for
thrombosis in bevacizumab therapy was that vascular endothelial growth factor (VEGF)
blockade leads to vascular inflammation and clotting. An alternate hypothesis was developed
by Meyer et al. (2009) who thought that this might be the result of platelet activation medi-
ated via the FcgRIIa (IgG) receptor - which is not present on mouse platelets - and aimed to
identify the functional roles of heparin and platelet surface localization in bevac izumab
-induced FcgRIIa activation. These studies demonstrated bevacizumab immune complexes
(IC) activating platelets via FcgRIIa in vitro. They followed these observations in vivo using
FcgRIIa (hFcR) transgenic mice. As predicted, bevacizumab IC was thrombotic in hFcR mice
in the presence of heparin. Furthermore, this activity required the heparin-binding domain of
bevacizumab’s target, VEGF. Heparin promoted bevacizumab IC deposition on to platelets in
a mechanism similar to that observed with antibodies from patients with heparin-induced
thrombocytopenia. When subactive amounts of ADP or thrombin were used to prime plate-
lets (simulating hypercoagulability in patients), bevacizumab IC-induced dense granule
release was significantly potentiated, and much lower (subtherapeutic) heparin concentra-
tions were sufficient for bevacizumab IC-induced platelet aggregation.
LY2541546 (antisclerostin) case study
Mild to severe decreases in platelets as off-target effects were observed during no nclinical
in vivo testing of mAbs against IL-13, IgE, sclerostin, and an unspecified cell-based target
(Rudmann et al., 2012; Martin et al., 2008; Everds et al., 2013). LY2541546, a humanized
mAb (IgG4) that had been optimized for neutralizing activity against sclerostin, caused
4. Early de-risking strategy for biotherapeutics120
I. Development of biopharmaceuticals
dose dependent, reversible decreases in platelet counts accompanied by accelerated platelet
production, increased megakaryocytes, and altered megakaryocyte morphology in 5-week
and 6-month nonclinical safety studies in rats. However, chronic or subchronic administra-
tion of LY2544156 to cynomolgus monkeys did not induce changes in platelet counts or
megakaryocytes. In vitro cross-reactivity studies in rats, cynomolgus monkeys, and humans
revealed LY2541546 bound rat but not cynomolgus monkey or human platelets and megakar-
yocytes. The species-specific nature of these reversible toxicologic findings combined with the
ease of clinical monitoring using standard hematology enabled the safe initiation of clinical
studies in human volunteers.
Omalizumab case study
In September 2000, US FDA requested that Genentech and Novartis suspend new trials of
omalizumab (Omalizumab, 2002). However, existing long-term trials could continue. The
hold on new trials was due to concerns about the nonclinical toxicity of omalizumab and
the follow-up antibody E26. Thrombocytopenia was reported in studies in monkeys for oma-
lizumab at 5 to 27 times the maximum clinical dose and for E26 at 3 to 15 times the maximum
dose. In response to FDA requests, Novartis and Genentech carried out additional nonclinical
trials so that a specific explanation of the toxicity could be obtained; they suspected a species
specificity for the adverse events, as no thrombocytopenic events occurred in the completed
Phase 3 clinical trials. The supplementary data were submitted to the FDA and the hold on
clinical trials was lifted in November 2000.
AMG X case study
AMG X, a human neutralizing mAb against a soluble human protein, caused thrombocy-
topenia, platelet activation, reduced mean arterial pressure, and transient los s of conscious-
ness in cynomolgus monkeys after the first intravenous administration (Everds and
Tarrant, 2013). In vitro, AMG X induce d activation in platelets from macaque species but
not from humans or baboons. Other similar mAbs against the same pharmacological target
failed to induce these in vivo and in vitro effects. In addition, the target protein was known
to not be expressed on platelets, suggesting that platelet activation occurred through an off-
target mechanism. AMG X bound directly to cynomolgus platelets and required both the Fab
and Fc portion of the mAb for platelet activation. Binding to platelets was inhibited by pre-
incubation of AMG X with its pharmacological target or with antihuman Fc antibodies or by
preincubation of platelets with AMG X F(ab’ ) or human immunoglobulin (IVIG). AMG X
F(ab’)(Bumbaca et al., 2011) did not activate platelets. Thus, platelet activation required
both recognition/binding of a platelet ligand with the Fab domain and interaction of platelet
Fc receptors (i.e., FcgRIIa) with the Fc domain. These findings reflect the complexity of the
mechanism of action of mAbs and the increasing awareness of potential for unintended ef-
fects in nonclinical species (Santostefano et al., 2012).
mAbY.1 case study
Cynomolgus monkeys dosed with a therapeutic mAb (mAbY.1) at 50 mg/kg had unex-
pected acute thrombocytopenia (nadir w3000 platelets/mL), sometimes with decreases in red
cell mass (Stebbings et al., 2007). Increased activated macrophages, mitotic figures, and eryth-
rophagocytosis were observed in the spleen. Binding of mAbY.1 to cynomolgus peripheral
Can we better address potential off-target toxicity? 121
I. Development of biopharmaceuticals
blood cells could not be detected in vitro. mAbY.1 induced phagocytosis of platelets by pe-
ripheral blood monocytes from cynomolgus monkeys, but not from humans. Monoclonal an-
tibodies sharing the same constant domain (Fc) sequences, but differing from mAbY.1 in their
variable domains, bound competitively to and had similar biological activity against the
intended target. None of these antibodies had hematologic liabilities in vitro or in vivo.
Neither the F(ab’)2 portion of mAbY.1 nor the F(ab’)2 portion on an aglycosylated Fc
(IgG1) framework caused phagocytosis of platelets in vitro. These data suggest the hemato-
logic effects of mAbY.1 in cynomolgus monkeys likely occurred through an off-target mech-
anism, shown to be driven by one to three amino acid differences in the light chain. This
example demonstrates that nonclinical safety studies can identify off-target effects of mAbs
prior to clinical trials (Everds and Tarrant, 2013; Everds et al., 2013).
Summary
Designing robust safety evaluation programs for biotherapeutics can be challenging and
must take account of the likelihood that many biotherapeutics will interact with the immune
system based on their modality, target and treatment populations. A range of tests can be per-
formed with human blood/cells/tissue and in pharmacologically relevant animal models to
both reduce the risk of some types of immunotoxicity occurring in humans and to charac-
terize the immunopharmacological and immunotoxicological effects of biotherapeutics. As
the knowledge base within companies and among regulators evolves in developing bio-
therapeutics, concomitant with advances in scientific understanding of the se entities through
clinical and laboratory experience, more relevant test systems will be developed and put into
use for predicting safety. This will allow a better understanding of the expected immunolog-
ical effects in humans and the likely immunotoxicological consequences in FIH studies and
beyond. For high-risk biologics, regulatory guidance has highlighte d the importance of using
PK-PD modeling in the selection of starting doses in FIH within the MABEL principles
(CHMP, 2018). Given the shortcomings of nonclinical animal models to predict cytokine
storm there is a need for the development of and standardization of tests for the prevention
or early detection of immunotoxicity in humans.
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